Review: Fluid biomarkers in the human prion diseases

Abstract

The human prion diseases are a diverse set of often rapidly progressive neurodegenerative conditions associated with abnormal forms of the prion protein. We review work to establish diagnostic biomarkers and assays that might fill other important roles, particularly those that could assist the planning and interpretation of clinical trials. The field now benefits from highly sensitive and specific diagnostic biomarkers using cerebrospinal fluid: detecting by-products of rapid neurodegeneration or specific functional properties of abnormal prion protein, with the second generation real time quaking induced conversion (RT-QuIC) assay being particularly promising. Blood has been a more challenging analyte, but has now also yielded valuable biomarkers. Blood-based assays have been developed with the potential to screen for variant Creutzfeldt-Jakob disease, although it remains uncertain whether these will ever be used in practice. The very rapid neurodegeneration of prion disease results in strong signals from surrogate protein markers in the blood that reflect neuronal, axonal, synaptic or glial pathology in the brain: notably the tau and neurofilament light chain proteins. We discuss early evidence that such tests, applied alongside robust diagnostic biomarkers, may have potential to add value as clinical trial outcome measures, predictors of future disease course (including for asymptomatic individuals at high risk of prion disease), and as rapidly accessible and sensitive markers to aid early diagnosis.

Detection of Cell-Free Mitochondrial DNA in Cerebrospinal Fluid of Creutzfeldt-Jakob Patients

“…CJD is the most frequent human transmissible spongiform encephalopathies (2–4). CJD can be confirmed by subjecting brain tissue from CJD patients to western blotting after digestion with proteases that is a demonstration of the protease resistance of the prion protein accumulated, or to use immunohistochemistry, abnormal PrP can be identified by its abundance, location and morphology (5). A diagnosis of pre-mortem CJD can be made based on autosomal dominant pathogenic mutations in the human prion protein gene ( PRNP) (6) and using real-time quaking induced conversion (RT-QuIC) which detected the accumulation of misfolded PrP in the brain, CSF, or nasal brushings (7), combined with clinical manifestations, medical history, epidemiological reports, EEG, and MRI (8, 9).…”

Optimization of the Real-Time Quaking-Induced Conversion Assay for Prion Disease Diagnosis

“…The lag phase (less than 20 h) and the detection times (2-day reduction in average detection time) were significantly reduced in the second generation of the RT-QuIC (Foutz et al, 2017;Franceschini et al, 2017;Groveman et al, 2017), which is comparable to the optimized protocol with PK treatment. Moreover, the sensitivity of the RT-QuIC could be increased (up 94%, 113 CJD cases were tested) without loss of specificity (100%; Foutz et al, 2017;Franceschini et al, 2017;Groveman et al, 2017;Thompson and Mead, 2019).…”

Altered DNA methylation profiles in blood from patients with sporadic Creutzfeldt-Jakob disease

“…More recently, extensive research has been directed towards identification of specific and selective biomarkers such as metabolites or proteins. To date, these efforts have largely concentrated on altered protein concentrations, or the real-time quaking induced conversion assay using CSF [59]. The need for biomarkers in easily accessible tissues such as blood is important because such tests could help make diagnoses and prognoses earlier and screen individuals before invasive procedures, tissue or blood donation.…”